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The Rare IL22RA2 Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis

Gómez-Fernández, Paloma ; Lopez de Lapuente Portilla, Aitzkoa LU ; Astobiza, Ianire ; Mena, Jorge ; Urtasun, Andoni ; Altmann, Vivian ; Matesanz, Fuencisla ; Otaegui, David ; Urcelay, Elena and Antigüedad, Alfredo , et al. (2020) In Cells 9(1).
Abstract

The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 × 10-4). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096,... (More)

The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 × 10-4). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%-60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.

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organization
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Contribution to journal
publication status
published
subject
keywords
Adult, Amino Acid Sequence, Computer Simulation, Databases, Genetic, Gene Frequency/genetics, Genetic Predisposition to Disease, HEK293 Cells, Humans, Middle Aged, Multiple Sclerosis/genetics, Polymorphism, Single Nucleotide/genetics, Protein Isoforms/genetics, Protein Sorting Signals/genetics, Receptors, Interleukin/chemistry, Risk Factors
in
Cells
volume
9
issue
1
publisher
MDPI Multidisciplinary Digital Publishing Institute
external identifiers
  • scopus:85098661001
  • pmid:31936765
ISSN
2073-4409
DOI
10.3390/cells9010175
language
English
LU publication?
yes
additional info
These authors contributed equally to this paper: Paloma Gómez-Fernández; Aitzkoa Lopez de Lapuente Portilla
id
cda303bc-6eef-4a68-9a91-975a89df9463
date added to LUP
2021-01-17 19:01:46
date last changed
2021-04-13 09:16:31
@article{cda303bc-6eef-4a68-9a91-975a89df9463,
  abstract     = {<p>The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 × 10-4). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%-60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.</p>},
  author       = {Gómez-Fernández, Paloma and Lopez de Lapuente Portilla, Aitzkoa and Astobiza, Ianire and Mena, Jorge and Urtasun, Andoni and Altmann, Vivian and Matesanz, Fuencisla and Otaegui, David and Urcelay, Elena and Antigüedad, Alfredo and Malhotra, Sunny and Montalban, Xavier and Castillo-Triviño, Tamara and Espino-Paisán, Laura and Aktas, Orhan and Buttmann, Mathias and Chan, Andrew and Fontaine, Bertrand and Gourraud, Pierre-Antoine and Hecker, Michael and Hoffjan, Sabine and Kubisch, Christian and Kümpfel, Tania and Luessi, Felix and Zettl, Uwe K and Zipp, Frauke and Alloza, Iraide and Comabella, Manuel and Lill, Christina M and Vandenbroeck, Koen},
  issn         = {2073-4409},
  language     = {eng},
  month        = {01},
  number       = {1},
  publisher    = {MDPI Multidisciplinary Digital Publishing Institute},
  series       = {Cells},
  title        = {The Rare IL22RA2 Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis},
  url          = {http://dx.doi.org/10.3390/cells9010175},
  doi          = {10.3390/cells9010175},
  volume       = {9},
  year         = {2020},
}